A Study of TransCon TLR7/8 Agonist With or Without Pembrolizumab in Patients With Advanced or Metastatic Solid Tumors

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Ascendis Pharma Oncology Division A/S

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

29 Jun 2023 → 3 Dec 2025

Decision date (initial)

2024-10-03

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-517150-10-00

EudraCT number

2021-001403-33

ClinicalTrials.gov

NCT04799054

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Dose response, Efficacy, Pharmacokinetic, Pharmacogenomic, Pharmacodynamic, Safety

To evaluate the safety and tolerability, and define the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of TransCon TLR7/8 Agonist alone or in combination with pembrolizumab

Part 3 Neoadjuvant Cohorts (Cohorts 3c and 3d): To evaluate the antitumor activity of TransCon TLR7/8 Agonist in combination with pembrolizumab

Secondary objectives 2

1. To evaluate the anti-tumor activity of TransCon TLR7/8 Agonist alone or in combination with pembrolizumab
2. To characterize the plasma pharmacokinetics of resiquimod, O-desethyl resiquimod, and total resiquimod (unbound + bound) after IT administration of TransCon TLR7/8 Agonist alone or in combination with pembrolizumab

Conditions and MedDRA coding

Cancer

Study design 3 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

1. At least 18 years of age
2. Participants who have previously received an immune checkpoint inhibitor prior to enrollment must have any immune related toxicities resolved to ≤Grade 1 or baseline (prior to the checkpoint inhibitor) to be eligible
3. Female and male participants of childbearing potential who are sexually active must agree to use highly effective methods of contraception
4. Participants must have histologically confirmed locally advanced, recurrent or metastatic solid tumor malignancies that cannot be treated with curative intent (surgery or radiotherapy), with the exception of participants enrolling to the neoadjuvant cohorts
5. Participants must have progressed on or be intolerant of available SOC treatment options or have disease for which there is no SOC treatment available, with the exception of participants enrolling to the neoadjuvant cohorts
6. At least 2 lesions of measurable disease, unless specified otherwise in the selection criteria.
7. Willingness to undergo biopsies
8. Demonstrated adequate organ function within 28 days of Cycle 1 Day 1 (C1D1)
9. Life expectancy >12 weeks as determined by the Investigator
10. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
11. Participants who have undergone treatment with anti-PD-1, anti-PDL1, or anti CTLA 4 antibody must have at least 4 weeks from the last dose of antibody and evidence of disease progression per investigator assessment before enrollment
12. Part 3 HNSCC 1. Histologically confirmed squamous cell cancers, regardless of HPV or PD-L1 status. 2. Known HPV (for example, p16 IHC) status. 3. Participants must have received no more than 1 prior line of chemotherapy-based treatment for locally advanced, unresectable, recurrent or metastatic disease. a. Cetuximab is not considered chemotherapy in this protocol
13. Part 3 Other HPV-Associated Tumor Types 1. Histologically confirmed anal, vulvar, cervical, penile or vaginal cancers. 2. Known HPV (for example, p16 IHC) status. 3. Participants must have received no more than 1 prior line of therapy (treatment regimen) for locally advanced, unresectable, recurrent or metastatic disease
14. Part 3 Neoadjuvant Melanoma 1. Histologically or cytologically confirmed diagnosis of cutaneous melanoma belonging to one of the AJCC TNM stages. 2. No prior radiotherapy or systemic anticancer therapy for melanoma. 3. At least one measurable lesion per RECIST v1.1 that is ≥15 mm in the longest diameter at time of selection.
15. Part 3 Neoadjuvant Cutaneous Squamous Cell Carcinoma 1. Histologically or cytologically confirmed locally advanced (high-risk) cutaneous squamous cell carcinoma as defined as: NOTE: Patients are eligible for this trial either at initial presentation for cSCC with locally advanced and/or concurrent regional nodal metastasis, assuming the criteria are met per the cSCC-specific AJCC UICC 8th edition staging classification. 2. At least one lesion measurable per RECIST v1.1 that is ≥15 mm in the longest diameter at time of selection

Exclusion criteria 18

1. Participants who have been previously treated with a TLR agonist (excluding topical agents for unrelated disease) are not eligible.
2. Other active malignancies within the last 2 years are excluded.
3. Active autoimmune diseases, regardless of need for immunosuppressive treatment at the time of screening, with the exception of patients well controlled on physiologic endocrine replacement.
4. Systemic immunosuppressive treatment with the exception for patients on corticosteroid taper (for example, for chronic obstructive pulmonary disease exacerbation). Participants cannot start dosing on study until steroid dose is at or lower than 10 mg per day prednisone or equivalent.
5. Women who are breastfeeding or have a positive serum pregnancy test during screening or within 72 hours prior to C1D1 are not eligible.
6. Vaccination with live, attenuated vaccines within 4 weeks of enrollment.
7. Symptomatic central nervous system metastases.
8. Known bleeding disorder that is deemed to place the patient at unacceptable risk for bleeding complications from intratumoral injections or biopsies.
9. Known hypersensitivity to any component of TransCon TLR7/8 Agonist or pembrolizumab.
10. Any uncontrolled bacterial, fungal, viral, or other infection.
11. Treatment with any other anti-cancer systemic treatment (approved or investigational) or radiation therapy within 4 weeks of first dosing on study is not allowed.
12. Significant cardiac disease.
13. A marked baseline prolongation of QT/QTc (corrected QT) interval (e.g., repeated demonstration of a QTc interval >480 ms (National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events [CTCAE] grade 1) using Fredericia's QT correction formula.
14. A history of additional risk factors for Torsades de Pointes (TdP) (e.g., heart failure, clinically significant hypokalemia, family history of Long QT Syndrome).
15. The use of concomitant medications that prolong the QT/QTc interval within 14 days of enrollment.
16. Positive for HIV or with active hepatitis B or C infection.
17. Part 3 Neoadjuvant Melanoma 1. Disease that is deemed unresectable is excluded. 2. Participants with acral/lentiginous, mucosal, or uveal melanoma are excluded.
18. Part 3 Neoadjuvant Cutaneous Squamous Cell Carcinoma 1. Patients whose tumor burden, or pace of tumor growth, in the opinion of the Principal Investigator will not permit delaying surgery. 2. Previous solid organ transplantation or bone marrow transplantation.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. All Parts: Incidence and severity of serious adverse events and adverse events
2. Parts 1 and 2 Dose Escalation Cohorts: Incidence of dose limiting toxicities (DLTs)
3. Part 3 Neoadjuvant Cohorts (Cohorts 3c and 3d): Pathologic complete response (pCR) per local assessment for pathology review

Secondary endpoints 12

1. Parts 1 and 2, and Part 3 HNSCC and other HPV-associated tumor types Cohorts (Cohorts 3a and 3b) − Objective response rate (ORR) by RECIST 1.1, duration of response (DoR) and TTR (time to response) per independent central review (ICR).
2. Parts 1 and 2, and Part 3 HNSCC and other HPV-associated tumor types Cohorts (Cohorts 3a and 3b) - ORR by RECIST 1.1, DoR and TTR per investigator assessment
3. Parts 1 and 2, and Part 3 HNSCC and other HPV-associated tumor types Cohorts (Cohorts 3a and 3b) − ORR for overall tumor burden, injected and noninjected lesions by itRECIST, DoR, and TTR per investigator assessment
4. Parts 1 and 2, and Part 3 HNSCC and other HPV-associated tumor types Cohorts (Cohorts 3a and 3b) - Progression free survival (PFS) by RECIST 1.1 per ICR
5. Parts 1 and 2, and Part 3 HNSCC and other HPV-associated tumor types Cohorts (Cohorts 3a and 3b) - PFS by RECIST 1.1 per investigator assessment
6. Parts 1 and 2, and Part 3 HNSCC and other HPV-associated tumor types Cohorts (Cohorts 3a and 3b) - Overall survival (OS)
7. Part 3 Neoadjuvant Cohorts (Cohorts 3c and 3d) − pCR per central assessment for pathology review
8. Part 3 Neoadjuvant Cohorts (Cohorts 3c and 3d) − Major pathologic response (MPR) per local assessment for pathology review
9. Part 3 Neoadjuvant Cohorts (Cohorts 3c and 3d) − MPR per central assessment for pathology review
10. Part 3 Neoadjuvant Cohorts (Cohorts 3c and 3d) − Event free survival (EFS) by RECIST 1.1 per investigator assessment
11. Part 3 Neoadjuvant Cohorts (Cohorts 3c and 3d) - OS
12. TransCon TLR7/8 Agonist PK parameters

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Ascendis Pharma Oncology Division A/S

Sponsor organisation

Ascendis Pharma Oncology Division A/S

Address

Tuborg Boulevard 12

City

Hellerup

Postcode

2900

Country

Denmark

Scientific contact point

Organisation

Ascendis Pharma Oncology Division A/S

Contact name

Joan Morris

Public contact point

Organisation

Ascendis Pharma Oncology Division A/S

Contact name

Joan Morris

Third parties 16

Locations

2 EU/EEA countries · 12 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 16 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications